Pharmacokinetic study of a new formulation of elacridar

Elacridar:
Elacridar is the most potent oral PgP/BCRP inhibitor, but unfortunately no
longer available for clinical trials. Therefore our pharmacy developed a new
elacridar formulation.

Purpose of elacridar development:
We need a potent PgP/BCRP inhibitor with high systemic exposure to ensure
maximal inhibitory effects at the site of the blood brain barrier. We
hypothesize that, when tyrosine kinase inhibitor (TKI; class of anticancer
agents) treatment is combined with an inhibitor of PgP and BCRP, such as
elacridar, TKI concentrations in the central nervous system (CNS) will increase
and the development of brain metastases may be prevented.

Ultimately, this healthy volunteer study will result in the possibility to
conduct a study combining elacridar with C11-labeled erlotinib. Using PET scans
we can study whether erlotinib (or other TKIs) can pass the blood brain barrier
and enter the brain when elacridar is given as an auxiliary drug. This can then
be used in the treatment of brain metastases and brain tumors.

To determine the pharmacokinetic properties of a new elacridar formulation

Phase I pharmacokinetic exploration study

Subjects will receive a single oral dose of elacridar.
Pharmacokinetic samples will be drawn after dosing at
T= 0, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 12, 24, 48 hours.

PK curves of the new elacridar formulation will be compared with historic PK
curves of the GSK elacridar tablets from earlier trials in our department and
from the literature.

Dosing will start with 25 mg in three healthy volunteers. After the first 3
healthy volunteers the following dose levels will be discussed by an internal
expert board. Dose will not exceed 1000 mg (which is known to be safe in humans
using the GSK tablet formulation)
The internal expert board at least consists of a preclinical elacridar expert
(Dr O. van Tellingen), a pharmacist/clinical pharmacologist and
pharmacokinetics expert (Dr. A. Huitema), and a medical oncologist/clinical
pharmacologist (Dr N. Steeghs).
The dose level defining the dose used for future studies will be expanded to a
total of 6 healthy volunteers.

The study is stopped when the target exposure is reached, when further
dose-increase does not result in further increase in systemic exposure (as in
the case of non-linear oral PK), or when dose limiting toxicity is observed.

Tablets containing 25 mg of a new elacridar formulation are used. All subjects
will receive one single administration of one or multiple tablets(depending on
dose level). Starting dose level is 25 mg. The maximum dose is set at 1000 mg.

Elacridar
Elacridar can be safely given in doses up to 1000 mg without side effects.
Elacridar shows very limited side effects in animal as in human studies (data
GSK on file). Elacridar is given in over 300 healthy volunteers and over 2000
cancer patients. Adverse events were predominantly mild in nature and all
resolved. The most common events were neurological (headache, somnolence,
dizziness, and tiredness) and gastrointestinal (diarrhea, gas, dyspepsia,
nausea and vomiting, abdominal discomfort). No serious adverse events were seen
in the healthy volunteer studies.

Blood samples:
Several blood samples will be drawn. Risks of this procedure is low. Some pain,
bruising and hematoma formation may occur. In rare ocasions an vein infection
or collaps may occur.